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Synthesis method for cariprazine

a synthesis method and cariprazine technology, applied in the field of medical technology, can solve the problems of difficult purification, low production efficiency of cariprazine, unsuitable for large-scale production, etc., and achieve the effects of mild reaction conditions, short reaction time and simple post-treatmen

Active Publication Date: 2021-09-30
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present application provides a cariprazine synthesis method with the following technical effects: short reaction time, simple post-treatment, mild reaction conditions, significantly reduced double-condensation impurity content, and a high product purity of more than 99.0%. The method is suitable for both small-scale laboratory preparation and large-scale industrial production.

Problems solved by technology

This impurity has poor solubility and is difficult to be purified; and the aforementioned synthesis method of cariprazine has low production efficiency and is not suitable for large-scale production.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Cariprazine

[0032]20 g (56 mmol, 1.0 eq) of compound I, 300 ml of dichloromethane, and 60 ml of 20 wt % sodium hydroxide solution were added to a 1000 mL three-necked flask, and 9.1 g (84 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 12 hours at 20-30° C. It was detected by HPLC that the raw materials had reacted completely, and the content of double-condensation impurity was 0.08%. After liquid separation of the reaction system and removal of a water phase, a dichloromethane phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate part of the dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 21.8 g of powdered solids (the cariprazine content was 99%, the purity was 99.5%, the double-condensation impurity content was 0.06%), with a yield of 90.9%.

example 2

on of Cariprazine

[0033]10 g (28 mmol, 1.0 eq) of compound I, 200 ml of dichloromethane, and 470 ml of 10 wt % potassium carbonate solution were added to a 1000 mL three-necked flask, and 4.5 g (42 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 15 hours at 20-30° C. It was detected by HPLC that the raw materials had reacted completely. After liquid separation of the reaction system and removal of a water phase, a dichloromethane phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate part of the dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 10.7 g of powdered solids (the cariprazine content was 99%, the purity was 99.3%, the double-condensation impurity content was 0.09%), with a yield of 89.2%.

example 3

on of Cariprazine

[0034]20 g (56 mmol, 1.0 eq) of compound I, 500 ml of dichloromethane, 36 ml of 20 wt % sodium hydroxide solution and 500 ml of 10 wt % sodium carbonate were added to a 1000 mL three-necked flask, and 9.1 g (84 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 13 hours at 15-25° C. It was detected by HPLC that the raw materials had reacted completely, and the content of double-condensation impurity was 0.07%. After liquid separation of the reaction system and removal of a water phase, a dichloromethane phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate part of the dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 22.3 g of powdered solids (the cariprazine content was 99%, the purity was 99.5%, the double-condensation impurity content was 0.06%), with a yield of 92.1%.

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Abstract

The present application relates to a synthesis method for cariprazine, comprising performing an acylation reaction between a compound represented by formula (I) and dimethylcarbamoyl chloride in a reaction solvent in the presence of an aqueous solution of an inorganic base, so as to obtain the cariprazine compound represented by formula (II). The synthesis method overcomes defects in the prior art such as a long reaction time, large size impurities and the difficulty of purification, and provides a new method suitable for commercial production wherein the reaction is fast, impurity sizes are small, the product is easily purified, the purity of the product can reach 99.0% or more, and the yield is high.

Description

[0001]The present application claims the priority of the Chinese patent application No. 201810993813.3, with the title of “SYNTHESIS METHOD FOR CARIPRAZINE”, filed on Aug. 29, 2018 before the China National Intellectual Property Administration, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present application belongs to the field of medical technology, and particularly relates to a synthesis method for cariprazine.BACKGROUND OF THE INVENTION[0003]Cariprazine, developed by original research Plc. Gedeon Richter (Gedeon Richter Ltd. Hungary), is a partial antagonist of dopamine D3 and D2 receptors and is used for the treatment of schizophrenia, bipolar disorder, bipolar depression and major depressive disorder.[0004]The US FDA approved cariprazine (trade name: Vraylar®) capsules for the treatment of schizophrenia and bipolar disorder in adult patients on Sep. 17, 2015. The European Commission approved the new antipsychotic drug Cariprazine fo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D295/135
CPCC07D295/135C07B43/06Y02P20/55
Inventor LIAO, WENJINGGE, JIANFENGZHANG, JICHENGHUANG, LUNINGTAO, ANPINGGU, ERIC
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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